Medical injection devices that comprise a sealing stopper in a gliding engagement within a container are widely used to deliver drug by injection to a patient.
Such injection devices include syringes, cartridges and auto-injectors.
Many different types of injection devices have been designed for administering medicines. Injection devices usually comprise a container intended to receive the product to be injected and a plunger rod intended to move a stopper within the container so as to expel the product therefrom at the time of injection. Empty and pre-filled disposable injection devices exist but prefilled devices are now preferred because they are more convenient and safer.
Such injection devices would be appropriate for containing new high-value drugs also commonly named “biotech” drugs that are currently developed and launched on the pharmaceutical market.
These biotech drugs can comprise for example biological elements such as proteins, peptides, DNA, RNA and the like, as well as sensitive compounds.
A major constraint with such drugs is their sensitivity towards their environment and therefore there is a need to find an appropriate container able to maintain the integrity of the drugs when they are stored for a long time in injection devices.
Traditional injection devices comprise a container made of glass or plastic and a stopper made of rubber.
Optionally, coatings can be applied on the surface of the container and/or on the surface of the stopper in order to improve the lubrication of the stopper inside the container.
But in some cases, it has been shown that such injection devices are not appropriate for long storage of high-value drugs due to the high and long term interaction with their containers.
Indeed, it has been shown that some degradations of the drug (aggregation, denaturing, unfolding, etc. . . . ) occur with time, leading to the withdrawal of the prefilled device out of the market and therefore leading to a high loss for pharmaceutical companies as well as leading to a risk for patients to be treated with degraded pharmaceutical drugs.
Therefore there is a need to have a prefilled injection device having a medical container compatible with biotech drugs, meaning a container that avoids any denaturing and/or aggregation of the drug after filling.
In addition, such prefilled injection devices should also have good gliding properties i.e. a low gliding force to move the stopper within the container.
Moreover, if a coating is applied on the surface of the prefilled injection device, the integrity of the coating has to be maintained from the deposition of the coating on the surface(s) of the medical device until the injection of the drug to the patient.
It means that any delaminating or breaking phenomena of the coating are to be avoided.
This is particularly the case for lubricant coatings that are commonly used to enhance the gliding properties of the injection devices.
Finally, the integrity of the drug, the integrity of the lubricant coating and the gliding properties of the prefilled device need to be maintained over time i.e. to be stable for at least the shelf life of the prefilled injection device.
Some documents such as U.S. Pat. No. 5,338,312 and EP 0 201 915, describe an injection device having enhanced gliding properties by using a lubricant coating that is cross-linked in order to immobilize the layer on the surface of the container of the injection device.
However, such injection devices are not necessarily compatible with sensitive drugs such as biotech drugs and/or vaccines.
Further, these documents do not address the issue of providing a coating that would keep its integrity within time and that would not have any significant or adverse interaction with the drug contained inside the injection device.
The document EP 1 060 031 describes a lubricated medical container that exhibits good gliding properties as well as low protein adsorption on the inner surface of the container.
Nevertheless, this document does not disclose any coating compatible with sensitive drugs such as vaccines and/or biotech drugs.
Indeed, as the coating described is not directed to be used with high-value drugs, even if the adsorption may be avoided, some denaturing of the drugs could occur.
This would be the case for example, with some polymers described in this document such as polymers with phosphorylcholine groups or poly-(2-hydroxyethyl methacrylate).
Additionally, this document does not disclose any information on a coating that keeps its integrity over time, after a long storage period.
However, the issue of storage is essential for prefilled syringes, as the lubricant coating needs to be stable over time not only before the filling of the drug in the injection device but also after the drug has been introduced in the injection device.
Recently, it has been demonstrated that particles can appear in the pharmaceutical composition after the filling of the container, due to interaction of the drug with the coating present on the inner wall of the container or on the surface of the stopper.
Generally speaking, silicone or silicone derivatives are often used as lubricant, and they have been identified as a main source of particle generation.
Indeed, specialists have observed that significant amounts of subvisible particles (i.e. particles having a size comprised between 0.1 μm and 100 μm) accelerate protein aggregation and unfolding.
Furthermore, sub-visible particles consisting of silicone, protein aggregates, or mixture of silicone with unfolded proteins and/or excipients may be hazardous for patients: it is thus recommended that the level of particles in this size range be carefully controlled.
One can refer in this respect to “Overlooking Subvisible Particles in Therapeutic Protein Products: Gaps That May Compromise Product Quality”, by John F. Carpenter et al., Journal of Pharmaceutical Sciences, Vol. 98, No. 4, April 2009.
These recommendations have been translated in more severe norms with regard to the maximum authorized particle level defined by the United States Pharmacopeia (USP 31 <788>) and the European Pharmacopeia (EP 6 <2.9.19>).
These norms not only place a heavy burden onto the pharmaceutical companies themselves but also onto the manufacturers of injection devices, since the release of particles from the containers into the pharmaceutical composition can occur and has to be avoided or at least dramatically reduced.
A goal of the invention is thus to provide a lubricant coating that exhibits a good compatibility with sensitive drugs stored inside a coated medical injection device for long time period in order to meet the pharmacopeia norms with regard to the level of particles in the drug, while still providing good performance with regard to the gliding of the stopper within the container of the medical injection device, and keeping its integrity over time.